New techniques, devices, and drugs for bleeding and/or haemorrhage control are being developed, particularly for severe bleeds. Despite all of the technology currently available, bleeding and haemorrhage control is still a major unresolved problem in emergency medical care. Almost 50% of all deaths in the first 48 hours of hospitalization are related to an inability to adequately control bleeding. Failure to stop bleeding within the first 24 hours is almost always fatal, especially when multiple trauma sites are involved. It is generally accepted that hemostatic products for forward care in a battle zone must control bleeding quickly, be ready to use, simple to apply, have a shelf life at ambient temperatures approaching two years and ideally prevent bacterial growth or viral transmission/reactivation. The product's hemostatic action is time-critical in order to meet both military and civilian needs.
Devices being investigated or used today as external methods of wound treatment range from absorbent pads containing clotting agents, pressure bandages, gauze, tourniquets for extremities, and trauma kits for wounds to the body.
Agents designed to stop external bleeding differ in composition and components but are often designed to help the rapid formation of a clot at the site of application. Clotting products generally contain varying but often high concentrations of materials such as human fibrinogen, thrombin, calcium, factor XIII and/or anti-fibrinolytics. In addition to fibrin, microporous polysaccharide macrobeads, mineral and synthetic zeolites, and chitosan (poly-N-acetyl glucosamine) are also available for use as hemostats. A number of new hemostatic products are available for treating wound trauma, for example, a bandage product using chitosan (deacetylated poly-N-acetyl glucosamine base, HemCon Inc., Tigard, USA), which is a freeze-dried chitosan dressing purportedly designed to optimize the mucoadhesive surface density and structural integrity of the chitosan at the site of the wound. The HemCon™ Chitosan Bandage apparently exerts its hemostatic effects primarily through adhesion to the wound, although there is evidence suggesting it may also enhance platelet function and incorporate red blood cells into the clot it forms on the wound. This bandage has shown improved hemostasis and reduced blood loss in several animal models of arterial haemorrhage, but a marked variability was observed between bandages, including the failure of some due to inadequate adherence to the wound. (See McManus et al, Business Briefing: Emergency Medical Review 2005, at 79). However, it only has a shelf life of 18 months. Another product based on chitosan is the Rapid Deployment Hemostat™ (RDH), (Marine Polymer Technologies, Danvers, USA), which appears to exert its hemostatic effect through red blood cell aggregation, platelet activation, clotting cascade activation and local vasoconstriction. The Rapid Deployment Hemostat™ is an algae-derived dressing composed of poly-N-acetyl-glucosamine. While the original dressing design was effective in reducing minor bleeding, it was necessary to add gauze backing in order to reduce blood loss in swine models of aortic and liver injury. (See McManus et al, Business Briefing: Emergency Medical Review 2005, page 78).
Z-Medica Corporation, Connecticut, USA, market a pressure bandage product (QuikClot®) for use by U.S. troops. This product uses a granular, synthetic mineral zeolite to stop bleeding by adsorbing liquid and promoting clotting. However, QuikClot® generates heat that can cause burns if the bandage isn't applied correctly and the mineral material is not biodegradable and so therefore has to be surgically removed.
Another commonly used hemostatic product is Combat Gauze, a kaolin-coated surgical gauze that is currently used as the standard dressing in the US military.
Nycomed Pharma, Austria, market a matrix of equine collagen coated with human fibrinogen and thrombin, under the trade names of Tachocomb® and Tachosil, which are available for operating room use in many European countries. (See U. Schiele et al, Clin. Materials 9:169-177 (1992)). While these fibrinogen-thrombin dressings do not require the pre-mixing needed by liquid fibrin sealants, their utility for field applications is limited by the common need to pre-moisten the product with saline in order to render it suitably flexible for application to a bleeding sited. Indeed, their field utility has not been observed to date, and it is known that these dressings are also not effective against high pressure, high volume bleeding. (See Sondeen et al. Trauma 54:280-285 (2003)). Another dry fibrinogen/thrombin dressing for treating wounded tissue is disclosed in U.S. Pat. No. 6,762,336, from the American Red Cross (ARC). This particular dressing is composed of a backing material and a plurality of layers, the outer two of which contain fibrinogen (but no thrombin) while the inner layer contains thrombin and calcium chloride (but no fibrinogen). While this dressing has shown success in several animal models of hemorrhage, the bandage is fragile, inflexible, and has a tendency to break apart when handled (See McManus et al, Business Briefing: Emergency Medical Review 2005, page 78; Kheirabadi et al. Trauma 59:25-35 (2005)). The mixing of the fibrinogen and thrombin was found to be very critical on the freeze drying/manufacturing procedure, indicating that complete mixing of the fibrinogen and thrombin active components is essential for full efficacy of the product. This product has not yet been approved for marketing in either the US or the EU.
Other fibrinogen/thrombin-based dressings have also been proposed. For example, U.S. Pat. No. 4,683,142 discloses a resorptive sheet material for closing and healing wounds which consists of a glycoprotein matrix, such as collagen, containing coagulation proteins, such as fibrinogen and thrombin. U.S. Pat. No. 7,189,410 discloses a bandage composed of a backing material having thereon: (i) particles of fibrinogen; (ii) particles of thrombin; and (iii) calcium chloride. US 2008/003272 and WO 00/38752 disclose a fibrin glue in the form of a mixed granulate or granule mixture coated onto a supporting material. EP 0 059 265 discloses a collagen carrier, coated with fibrinogen and thrombin particles. WO 97/44015 discloses a thrombin/fibrinogen albumin microparticle mixture. WO 2010/002435 discloses a bioresorbable hemostatic pouch comprising fibrinogen or thrombin microparticles as well as glass microparticles in the core.
No perfect solution currently exists for the treatment of excessive or severe bleeding, particularly control of pressure bleeding from arterial or venous bleeding. Heat generation with respect to one type of agent is a major problem. Certain dressing's ability to adhere effectively when applied to deep wounds or wounds of irregular shape creates another major limitation.
Surgical and trauma wounds are the most common types of wounds addressed in the wound-care arena. A further hurdle to overcome when developing products for this field is the deleterious effect of anti-coagulants present in the blood of such surgical patients. Current bandages are made of gauze and are often applied in conjunction with an elastic bandage. They allow the wound to breath but are poor barriers to subsequent contamination. These bandages cannot stop serious bleeding and require the application of pressure in the case of arterial, diffuse or venous bleeding. Many conventional wound sealants fail to present an optimized combination of speed of clotting, effectiveness under high pressure bleeding conditions, and clots that are dynamic over time in response to the needs of the trauma site. Typically, wound sealants are usually used in conjunction with separate wound dressings. Clearly, surgical trauma caused by sharp objects occurs in a clean environment, often as a by-product of the surgical procedure itself. However, trauma wounds not caused in a controlled environment are often intermediate sized, widespread, and dirty wounds with considerable tissue damage are found in road traffic accidents or on the battlefield.
Abrasions are generally caused by scraping of the skin's outer layer; lacerations are jagged, irregular cuts or tears of the skin; punctures are caused by an object piercing the skin layers, creating a small hole; incisions are cuts commonly caused by knives or other sharp objects; and burns cause damage which may vary greatly in depth, size, and severity. Wounds due to firearms can be deep and with substantial tissue destruction. Dismemberment due to trauma requires immediate intervention to stop blood loss from the severed limb.
WO97/44015 only describes a dry powder fibrin sealant based on micro-particles of fibrinogen and thrombin. Further optimised formulations of these microparticle compositions are described in co-pending non-provisional application U.S. Ser. No. 12/636,718.
Accordingly, there remains a need in the art for a solid, ready-for-use (i.e. no reconstitution, mixing, etc.) dressing that can be used to treat wounded tissue, particularly wounded tissue resulting from traumatic injury in the field or in surgery, and/or similar severe bleeding situations. Additionally, there remains a need in the art for a solid and/or flexible or liquid (or viscous liquid), ready-for-use (i.e. no reconstitution, mixing, etc.) hemostatic sealant that can be used to treat wounds having difficult access or requiring space-filling properties. Other advantages of the present invention include improved handling and application in use, the reduced need to employ other hemostatic products and less need for application of additional exogenous microparticles present in the composition according to the invention.